PROJECT ABSTRACT Many genetic disorders are characterized by defects in neuronal function and cognitive ability. To gain key insights into new ways of approaching these diseases, it is critical to understand the molecular basis for regulating neuronal transcriptional programs and take advantage of emerging global genomic technologies, which provide deep insights into the molecular basis for these disorders. Here, we focus on a severe neurological disorder that is caused by mutations of the methyl-CpG-binding protein, MeCP2, and how it causes alterations in gene expression programs required for neuronal function. We propose to investigate this perplexing syndrome, which can be categorized under the umbrella of ?autism spectrum? disorders, to test a previously unappreciated mechanism for regulating neuronal transcription programs based on chromosomal architecture. Specifically, we will determine the effects of MeCP2 loss on chromatin architecture and its relation to changes in gene transcription, as well as determine the functional role of MeCP2 on the nuclear matrix-dependent architectural network. We will utilize several mouse genetic models to target several important brain cell types and apply genome wide methodologies to elucidate the contribution of each of these to the observed brain phenotype. We expect to expand our understanding of MeCP2-dependent transcriptional de- regulation due to structural effects on chromosome architecture, and uncover the role of MeCP2 in regulation of chromosomal boundary/ sub-nuclear architectural interactions as an underlying mechanism in Rett syndrome. This will enable new understanding of the molecular mechanisms of this devastating neurological disease, and lay the groundwork for potential new classes of potential therapeutic avenues.